Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID

NCT04797260 | Suspended Phase 1 DMC

• 3 other identifiers: RAG1-2019-012023-510204-50-002019-002343-14
• Study Type: interventional
• Target: 10
• Locations: 4 countries
• Sites: 4

Brief Summary

This trial is a prospective, non-randomized, open-label, multicentre single-arm phase I/II intervention trial in children up to 24 months of age with RAG1-deficient SCID and an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The trial involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in up to 10 patients with RAG1-deficient SCID. Patients will be regularly monitored for 5 years after infusion. Follow up as part of routine clinical care for post-transplant patients will be annual after this, for at least 15 years after IMP infusion.

Conditions

Severe Combined Immunodeficiency Due to RAG1 Deficiency

Keywords

SCID; RAG1; Gene Therapy

Outcome Measures

Primary Outcomes (3)

• To evaluate the effect of RAG1 gene therapy on overall survival.

  Overall survival

  5 years

• To evaluate the efficacy of RAG1 gene therapy in achieving reconstitution of the T and B cell immune system in patients with RAG1-SCID at 6 months.

  Evaluation of immune reconstitution at Month 6 defined as * Presence of naive CD4+ T cells * Total CD3+ T-cells \> 300 cells/μL * Total CD4+ T-cells \> 200 cells/μL

  6 Months

• To evaluate the safety and tolerability of the RAG1 gene therapy product, including identification of short- and long-term adverse events.

  * Number of patients with adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs, e.g. insertional mutagenesis) and relatedness of the events to intervention, treatment and/or investigational drug * Incidence of new or worsening abnormalities in laboratory safety parameters and clinical assessments (including hematology, biochemistry, endocrinology, physical examination findings, vital signs, cardiac ultrasound, and Lansky performance score).

  5 years

Secondary Outcomes (6)

• To evaluate the effect of RAG1 gene therapy on event-free survival.

  1 year

• To evaluate the efficacy of RAG1 gene therapy in achieving independence of Immunoglobulin substitution

  2 years

• To evaluate the long-term efficacy of RAG1 gene therapy in reconstituting the immune system in patients with RAG1-SCID.

  6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months

• To evaluate the pharmacodynamic effects of RAG1 gene therapy.

  6, 12, 18, 24, 30, 36, 42, 48, 54, 60 Months

• To evaluate the effects of RAG1 gene therapy on quality of life

  2 years

Study Arms (1)

Gene therapy

EXPERIMENTAL

In this arm, 10 patients will be included for gene therarpy

Genetic: Gene therapy

Interventions

Gene therapy GENETIC

Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).

Gene therapy

Eligibility Criteria

• Age: 8 Weeks - 24 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• RAG1-deficient SCID as confirmed by genetic analysis
• Peripheral blood CD3+T cells \< 300/μL
• Absence of peripheral blood naïve CD4+ T cells
• Age \< 2 years
• Age at least 8 weeks by the time of busulfan and fludarabine administration
• Lack of an available HLA-identical sibling/family donor
• Signed informed consent (parental or guardian)
• Able to return to the local HSCT centre for follow-up (per protocol) during the 5-year trial and up to at least 15-year long-term follow-up after IMP administration

You may not qualify if:

• Omenn syndrome
• Previous allogeneic HSCT
• Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):
• Mechanical ventilation
• Shortening fraction on echocardiogram \<25%
• Renal failure defined as dialysis dependence
• Uncontrolled seizure disorder
• Any other condition that the investigator considers is a contraindication to collection and/or infusion of trans-duced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits.
• Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection

Sponsors & Collaborators

• CR2O B.V.: collaborator
• Videja B.V.: lead

Study Sites (4)

Leiden University Medical Center

Leiden, 2300RC, Netherlands

Location

Wroclaw Medical University

Wroclaw, 50-556, Poland

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Erciyes Üniversitesi TIP Fakültesi

Kayseri, Turkey (Türkiye)

Location

Related Publications (1)

• Garcia-Perez L, van Eggermond M, van Roon L, Vloemans SA, Cordes M, Schambach A, Rothe M, Berghuis D, Lagresle-Peyrou C, Cavazzana M, Zhang F, Thrasher AJ, Salvatori D, Meij P, Villa A, Van Dongen JJM, Zwaginga JJ, van der Burg M, Gaspar HB, Lankester A, Staal FJT, Pike-Overzet K. Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID. Mol Ther Methods Clin Dev. 2020 Mar 31;17:666-682. doi: 10.1016/j.omtm.2020.03.016. eCollection 2020 Jun 12.

  PMID: 32322605 RESULT

MeSH Terms

Interventions

Genetic Therapy

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics; Genetic Engineering; Genetic Techniques; Investigative Techniques

Study Officials

• Arjan C Lankester, Prof.dr.

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants will receive a single administration of autologous gene-modified CD34+ hematopoietic stem cells, following ex vivo transduction with the pCCL.MND.coRAG1.wpre lentiviral vector. In case of failure of hematopoietic reconstitution after infusion, the autologous backup graft will be infused to rescue the patient from aplasia. Alternatively, a conventional allogeneic HSCT procedure may be scheduled. After infusion, participants will be followed for safety and efficacy over 5 years as per study protocol. Follow up as part of the routine clinical care for post-transplant patients will be annual after this, for at least 15 years after infusion.

Study Record Dates

• First Submitted: March 11, 2021
• First Posted: March 15, 2021
• Study Start: July 23, 2021
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031
• Last Updated: July 16, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1); NL (1); PL (1); ES (1)